Major depressive disorder (MDD) is a devastating mental illness arising from a combination of genetic, epigenetic, and environmental influences. Despite decades of investigation, our ability to diagnose and treat MDD remains limited, and a large fraction of MDD patients fail to respond to available treatment options. Epigenetic genome changes likely play a significant role in the pathophysiology of depression, especially since environmental stimuli and experience are important contributors to the development of MDD. We propose to couple technology development and circuit-specific epigenetic analysis of genome methylation and chromatin remodeling to reverse engineer the epigenetic mechanisms underlying major depressive disorder, and to discover novel drug targets for developing fundamentally new classes of antidepressants. Using animal models of depression we will identify specific circuits of cells in the brain whose functions are compromised in the disease state and determine the contributing epigenetic mechanisms. To enable the proposed research, we will develop an innovative platform of technologies to enable targeted genome and epigenome modifications and apply it to systematically identify epigenetic mechanisms in specific circuit components underlying depression. We will also explore the identified epigenetic mechanisms for developing new classes of antidepressants. In addition to our core technologies for genome and epigenome engineering, we will integrate a comprehensive range of technical expertise spanning electrophysiology, imaging, behavioral analysis, computational biology, synthetic biology, high-throughput genome and epigenome analysis, and highthroughput drug screening and assay development. The successful completion of our vision will yield four broad impacts: I. Pioneer a new approach for drug target discovery that has implications for a broad range of developmental and chronic illnesses. II. Develop a robust technology platform for large-scale targeted genomic engineering to enable more complete recapitulation of human disease genotypes in animal models. We will enable precise introduction of combinations of disease-associated genetic mutations into a single animal model. III. Develop a technology for targeted epigenome modification to enable direct functional testing of causal links between specific epigenetic modifications and disease pathophysiology. IV. Identify fundamentally new classes of therapeutics for major depression.
Major depressive disorder is a devastating mental illness affecting millions of Americans annually, with a large fraction of patients unresponsive to available therapies. The proposed project aims to identify fundamentally new classes of therapeutics by probing the epigenetic mechanisms contributing to major depression, through a combination of innovative technology development, and systematically establishing causal links between epigenetic targets and disease phenotype. The technologies developed through this proposal will establish a new epigenetic paradigm for drug discovery and have broad impacts for many fields of biomedical research including cancer, diabetes, obesity, and other neurological disorders.
|Slaymaker, Ian M; Gao, Linyi; Zetsche, Bernd et al. (2016) Rationally engineered Cas9 nucleases with improved specificity. Science 351:84-8|
|Tabebordbar, Mohammadsharif; Zhu, Kexian; Cheng, Jason K W et al. (2016) In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351:407-11|
|Yamano, Takashi; Nishimasu, Hiroshi; Zetsche, Bernd et al. (2016) Crystal Structure of Cpf1 in Complex with Guide RNA and Target DNA. Cell 165:949-62|
|Sanjana, Neville E; Wright, Jason; Zheng, Kaijie et al. (2016) High-resolution interrogation of functional elements in the noncoding genome. Science 353:1545-1549|
|Hirano, Hisato; Gootenberg, Jonathan S; Horii, Takuro et al. (2016) Structure and Engineering of Francisella novicida Cas9. Cell 164:950-61|
|Jain, Isha H; Zazzeron, Luca; Goli, Rahul et al. (2016) Hypoxia as a therapy for mitochondrial disease. Science 352:54-61|
|Abudayyeh, Omar O; Gootenberg, Jonathan S; Konermann, Silvana et al. (2016) C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector. Science 353:aaf5573|
|Nelson, Christopher E; Hakim, Chady H; Ousterout, David G et al. (2016) In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351:403-7|
|Heidenreich, Matthias; Zhang, Feng (2016) Applications of CRISPR-Cas systems in neuroscience. Nat Rev Neurosci 17:36-44|
|Zhou, Yang; Kaiser, Tobias; Monteiro, PatrÃcia et al. (2016) Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects. Neuron 89:147-62|
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